17alpha-ethinyl-18-methyl-19-nortestosterone esters



3,514,514 17a-ETHINYL-18-METHYL-19-N0RTEST0S- V TERONEESTERS Hans-Giinter L'elimann, Heinz Gibian, Rudolf Weichert, and Friedmund Neumann, Berlin, Germany, assignors to ScheringAktiengese'llschaft, Berlin, Germany No Drawing. Filed May 4, 1966, Ser. No.'547,438.

Claims pr'iority,- application Germany, May v5, 1965,

"- In. accordance with the pre'se'nt-invention, there are provided l7fl-monoesters and 3-e'riol-17B-die'sters 6f' 17aethinyl-l8 methyl' 19 -"'n'ortestosterone constitutingnew therapeutic compounds having outstanding properties. These compounds possess progestive activity .and are s Claims I active when administered orally or subcutaneously. They are readily solublein the conventional pharmaceutical carriers used jfor'jsteroid hormonesja'syforexample, vegetable oils such as sesame voil, castonoil, cotton seed oil,

sunfloweroilfolive bi], and the like, as well as in synthetic solvents, for instance, glycols, lactic acid esters, 'benzyl benzoate and the like. Because of their considerable solubility, it is possible to employ s'olution's of the esters of the invention'as' injectiblesand therebyalso to utilize them as hormone depots.

The activecor'n'pounds of the inveiitiori are prepared by reacting 17a-ethinyl-18-rnethyl l9-nortestosterone with an organic carboxylic acid or reactive derivative thereof in the conventional manner to produce the ester,The 3-enol ester group of the primarily formed 3-enol-17 8- diester is thereafter under regeneration of the 3-keto-A group partially saponified.

The new esters demonstrate central inhibiting activity and are accordingly suitable as highly effective ovulation inhibiting agents.

The ovulation inhibiting activity was demonstrated in normal female rats (Sprague-Dawley) where following oral administration the conventional tube inspection tests were carried out and established for l7a-ethinyl-18- methyl-19-nortestosterone-acetate a ED of only 3 mg. In comparison, the free l7a-ethinyl-18-methyl-19-nortestosterone had a ED of 10 mg. (the ED is that dosage which results in inhibition of ovulation in 50% of the experimental animals). Side effects such as weight gain, liver incompatibility or estrogen side reactions were not observed.

The new compounds accordingly are indicated as therapeutic agents for medical conditions where inducing a quiet state in the ovaries is recommended.

As further applications, the compounds can be used, for example, in the treatment of dysmenorrhea, endometriosis, cyclic disturbances, and functional sterility.

The compounds of the invention are administered in the conventional dosage forms, such as capsules, granulates, solutions, drages, and tablets and are compounded together with suitable pharmaceutical carriers. When tablets are prepared they may be made in various sizes (total weight of 50150 mg.) containing from about 0.1-0.5

mg. of the drug suitably in combination with another hormone component having estrogenic activity as, for instance, 0.05 mg. ethinyl estradiol. The tablets are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactone or the like. If desired, these tablets may be coated with sugar or shellac preparations ice in accordance with the common .practices in .the table manufacturingart., v In addition, the higher esters-are characterized by-an excellent and protracted activity. r 1 v The active compounds can be prepared bythe conventional methods of steroid chemistry. l, (j Theesterification with the desired acid canbe I conducted in an acid or an alkaline reaction medium. Asa result of the acid esterification, thereis directly produced the ,17-mono ,-ester.;There must, however, be accepted a higher loss of desired product as simultaneously withthe esterification an aromatization of the A-n'ng takes place. The undesired side reaction can be avoided through the intermediate protection of the 3-keto I group, 'forinstan'ce, by ketalizatiom Ths procedure implies'itwo steps'in the formation of the17-inono-1ester, "i.e., ketal formations'and ketalsplitfingfi j I t, v "Analternatereaction is the alkaline esterification effected in" the presence of ani'organic nitrogen base, as for instance pyridine, quinoline, etc., wherebythere'is produced as the primary gproducta 3-er'1ol-17fi-diacyl ester. The reaction mixture containing the primary productis further worked up, for example, by treatment with neutral ice water or extraction, or through prolonged stirring in alkaline ice water and the resulting 17-mono-acyl-ester isolated.

' For use in the esterification, any of the acids suitable in steroid chemistry can be used. Illustrative of suitable acids are aliphatic carboxylic acids having 1-11, and most preferably l-8, carbon atoms in the acid group, for example, acetic acid, propionic acid, caproic acid, onanthic acid, undecylic acid. The acids can be saturated or unsaturated, branched or not, polybasic or substituted in the known manner such as trimethylacetic, t.butylacetic, phenylacetic, cyclopentyl-propionic, halogen-acetic, aminoacetic, oxypropionic, benzoic, succinic, adipic acids, etc. The esterification is advantageously carried out at elevated temperatures, preferably at temperatures of from 130- 200 C. The time required for the reaction is directly dependent on the reaction temperature. Thus the diester is produced after 6 hours with a reaction temperature of 160 C. and in 5 hours with a reaction temperature of 170 C. The said diester, i.e., 3-enol-17,B-diacyl ester is thereafter partially saponified in the 3-position.

The following examples are given in order to disclose more clearly the nature of the present invention. It should be understood, however, that the examples are not intended to be a limitation on the scope of the invention.

EXAMPLE 1 EXAMPLE 2 400 mg. 17a-ethinyl-l8-A -estradiene-3,17,3-diol-diacetate were admixed with 400 mg. sodium bicarbonate in 40 ml. methanol and 4 ml. water and the mixture stirred at room temperature for 6 hours. Thereafter, the reaction mixture was poured into ice water and neutralized with glacial acetic acid. The precipitate which formed was separated off by filtration, washed with water and dried. There were thereby produced 350 mg. crude 17a-ethinyl-18- methyl-19-nortestosterone acetate having a melting point hf-156-l57 C.Follhwingrecrjistallizationfrom ether,260 A -estradiene-3,17B diol-3,17fi diester, wherein the said 'mg? of the" acetate nreltingmt l 62 l63- wereobtainedr" "*Tfiestef'and *3,=1?[3=diester*'groups are formed" from ali- ""f a AQ liL fi I 2 v g. 17' e t ay'i-1' 8-methyl-l9-nortestosterone in 26 m1.

pyridine and 27g. caprdio'acidanhydridewere heated to- "gethen undera nitrogen atmosphere :for7 hours at 160 C. Following cooling, the reaction mixture which contained the primary formed l17a-ethinyl-18-methyl-19nortestosterone-3.-ei1ol-17 fl dicapronate was poured into bicarbonate'water and stirred for 3.0 hours to saponify the excess caproic acid anhydride. Followingfiltration, there were obtained 2.1 g. of an'oily crude product. The crude product was purified chromatographically using silica gel and resulted in the recovery of 1.6 g. l7a-ethiny1-18-methyl-19- nor-testosterone-caproate having a melting "point of 112- 113 C. After dissolution in pentane, there were recovered 1.5 g. of thecaproate having'an unchanged melting point.

'In place of the nitrogen there can be used other inert protective gases as, for instance, argon.

What is claimed is as follows:

1. A therapeutic compound for inhibiting ovulation comprising as active ingredient a compound selected from the group consisting of a 17-ester of 17u-ethinyl-18- methyl-19-nor-testosterone and a l7a-ethinyl-18-methylphatic carboxylic acids having from 1 to 11 carbon atoms in the ester residue; and a pharmaceutical carrier for said compound.

2. The compound of claim 1 which is th e,17B-.acetate of the said nortestosterone.

; 3. The compound. of claim 1 which is the.1.7fl-caproate ofthesaidnorte stosterone.

4. The compound of claim .1 which isIthe17 3-diacetate of the said estradiene. 'J-

5. The compound of claim' 1 which isjthe l'lfi-ca'p'roate of the said estradiene... 6 vA.,therapeutic composition for-inhibiting ovulation comprising as active ingredient the l7o ethinyl-l 8-rriethyl- 19-.no'rtestosterone esterd'efined in claim I in an amount of 0.1 'to 0.5 mg. and :in admixture with a pharmaceutical carrier.- 9 v I p 7. A therapeutic composition for inhibiting ovulation according to claim-,6, wherein said-ester is 17a=ethiny1+18- methyl-19-nortestosterone5acetate.

8. A method of, providing steroid therapy which com,- prises administering to a subject a therapeutic composition .accordingto claim 6. l .y a v r Y References Cited- "UNITED STATES PATENTS 2,601,287 6/1952 Heyl .et al. 260397.3

2,798,879 7/1957 Donia et al. 260-.-397.4 2,868,809 l/l959 Donia etal 260397.4 3,006,933 '10/1961 Allen et al. 260-397.45 3,231,589 1/1966 Greenspan et al. 260397.4

HENRY A. FRENCH, Primary Examiner I i us. c1. X.R. v 

1. A THERAPEUTIC COMPOUND FOR INHIBITING OVULATION COMPRISING AS ACTIVE INGREDIENT A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 17-ESTER OF 17A-ETHINYL-18METHYL-19-NOR-TESTORSTERONE AND A 17A-ETHINYL-18-METHYL$3,5-ESTRADIENE-3,17B-DIOL-3,17B-DIESTER, WHEREIN THE SAID 17-ESTER AND 3,17B-DIESTER GROUPS ARE FORMED FROM ALIPHATIC CARBOXYLIC ACIDS HAVING FROM 1 TO 11 CARBON ATOMS IN THE ESTER RESIDUE; AND A PHARMACEUTICAL CARRIER FOR SAID COMPOUND. 